scholarly journals Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuri Takada ◽  
Hiroaki Itoh ◽  
Atmika Paudel ◽  
Suresh Panthee ◽  
Hiroshi Hamamoto ◽  
...  
Keyword(s):  
Ion Channel ◽  
Large Scale ◽  
Antibacterial Activities ◽  
Gramicidin A ◽  
Ion Concentration ◽  
Peptide Antibiotic ◽  
Structure Activity ◽  
Common Ion ◽  
Multidimensional Screening ◽  
The Common

Abstract Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10 analogues share a similar ion channel function, but have different cytotoxic, hemolytic, and antibacterial activities. Our large-scale structure-activity relationship studies reveal the feasibility of developing analogues of 1 that selectively induce toxicity toward target organisms.

Structure of the ion channel peptide antibiotic gramicidin A

Biopolymers ◽  
1989 ◽  
Vol 28 (1) ◽  
pp. 259-266 ◽  
Author(s):  
David A. Langs
Keyword(s):  
Ion Channel ◽  
Gramicidin A ◽  
Peptide Antibiotic

Student Perceptions of Community: A Different Perspective

NASPA Journal ◽  
1998 ◽  
Vol 35 (4) ◽  
Author(s):  
Jackie Clark ◽  
Joan Hirt
Keyword(s):  
Student Perceptions ◽  
Large Scale ◽  
Research University ◽  
Small Scale ◽  
Social Environments ◽  
Common Assumption ◽  
Small Communities ◽  
Public Research University ◽  
The Common ◽  
Using Data

The creation of small communities has been proposed as a way of enhancing the educational experience of students at large institutions. Using data from a survey of students living in large and small residences at a public research university, this study does not support the common assumption that small-scale social environments are more conducive to positive community life than large-scale social environments.

scholarly journals A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency

2021 ◽  
pp. 247255522110181
Author(s):  
Andreas Vogt ◽  
Samantha L. Eicher ◽  
Tracey D. Myers ◽  
Stacy L. Hrizo ◽  
Laura L. Vollmer ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Large Scale ◽  
Protein Quality ◽  
Fluorescent Protein ◽  
Triose Phosphate Isomerase ◽  
Pharmacological Intervention ◽  
Screening Assay ◽  
Triose Phosphate ◽  
The Common ◽  
Green Fluorescent

Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia, and muscle weakness that quickly progresses with severe neuromusclar dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~5 years. There are several described pathogenic mutations that encode functional proteins; however, these proteins, which include the protein resulting from the “common” TPIE105D mutation, are unstable due to active degradation by protein quality control (PQC) pathways. Previous work has shown that elevating mutant TPI levels by genetic or pharmacological intervention can ameliorate symptoms of TPI Df in fruit flies. To identify compounds that increase levels of mutant TPI, we have developed a human embryonic kidney (HEK) stable knock-in model expressing the common TPI Df protein fused with green fluorescent protein (HEK TPIE105D-GFP). To directly address the need for lead TPI Df therapeutics, these cells were developed into an optical drug discovery platform that was implemented for high-throughput screening (HTS) and validated in 3-day variability tests, meeting HTS standards. We initially used this assay to screen the 446-member National Institutes of Health (NIH) Clinical Collection and validated two of the hits in dose–response, by limited structure–activity relationship studies with a small number of analogs, and in an orthogonal, non-optical assay in patient fibroblasts. The data form the basis for a large-scale phenotypic screening effort to discover compounds that stabilize TPI as treatments for this devastating childhood disease.

scholarly journals A NOTE ON PHASING LONG GENOMIC REGIONS USING LOCAL HAPLOTYPE PREDICTIONS

2006 ◽  
Vol 04 (03) ◽  
pp. 639-647 ◽  
Author(s):  
ELEAZAR ESKIN ◽  
RODED SHARAN ◽  
ERAN HALPERIN
Keyword(s):  
Large Scale ◽  
Computational Cost ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Novel Approach ◽  
Maximum Likelihood Criterion ◽  
The Common ◽  
Genomic Regions ◽  
High Computational Cost ◽  
Combining Information

The common approaches for haplotype inference from genotype data are targeted toward phasing short genomic regions. Longer regions are often tackled in a heuristic manner, due to the high computational cost. Here, we describe a novel approach for phasing genotypes over long regions, which is based on combining information from local predictions on short, overlapping regions. The phasing is done in a way, which maximizes a natural maximum likelihood criterion. Among other things, this criterion takes into account the physical length between neighboring single nucleotide polymorphisms. The approach is very efficient and is applied to several large scale datasets and is shown to be successful in two recent benchmarking studies (Zaitlen et al., in press; Marchini et al., in preparation). Our method is publicly available via a webserver at .

scholarly journals Redox-regulated ion channel activity of a cysteine-containing gramicidin A analogue

2006 ◽  
Vol 1758 (4) ◽  
pp. 493-498 ◽  
Author(s):  
Yuri N. Antonenko ◽  
Tatyana B. Stoilova ◽  
Sergey I. Kovalchuk ◽  
Natalya S. Egorova ◽  
Alina A. Pashkovskaya ◽  
...  
Keyword(s):  
Ion Channel ◽  
Gramicidin A ◽  
Channel Activity

Kinetics of hypso anhydrites dissolution in water. Experimental studies

2019 ◽  
pp. 93-96
Author(s):  
A. L. Lebedev ◽  
I. V. Avilina
Keyword(s):  
Experimental Data ◽  
Experimental Study ◽  
Riccati Equation ◽  
Balance Equation ◽  
Experimental Studies ◽  
Common Ion ◽  
The Common ◽  
Common Ion Effect ◽  
Kinetics Of Dissolution ◽  
Kinetics Of

Experimental study of kinetics of dissolution of hypso anhydrites at 25 ᵒC made it possible to formulate model of the process in the form of a balance equation for the kinetics of dissolution of gypsum, anhydrite (first and second orders, respectively) and kinetics of precipitation of gypsum (second order). The processing of the experimental data were carried out on the basis of the solution of the Riccati equation. When taking into account the common-ion effect on the solubility of gypsum and anhydrite, the calculated values turned out to be more comparable with the experimental ones.

scholarly journals Chloroform extraction of trace nutrients as oxinates from soil extracts for spectrographic analysis

1960 ◽  
Vol 32 (1) ◽  
pp. 223-228
Author(s):  
Osmo Mäkitie
Keyword(s):  
Trace Metals ◽  
Chloroform Solution ◽  
Soil Extract ◽  
Hydrogen Ion ◽  
Ion Concentration ◽  
Spectrographic Analysis ◽  
Hydrogen Ion Concentration ◽  
Soil Extracts ◽  
Copper Manganese ◽  
The Common

The experiments show that under these conditions the common trace nutrients, cobalt, copper, manganese, molybdenum and zinc are sufficiently completely extracted as chelates by shaking the soil extract with oxine-chloroform solution. The hydrogen ion concentration of the extract and the concentration of oxine in chloroform have decisive effects on the extractability. Using the reported and discussed procedure it is possible to separate the common trace metals from the major soil extract constituents, especially for spectrographic analysis.

PARAMETER IDENTIFICATION FOR ELECTROCHEMICAL MODELS OF LITHIUM ION BATTERIES USING SENSITIVITY ANALYSIS

2021 ◽  
pp. 1-33
Author(s):  
Chitra Dangwal ◽  
Marcello Canova
Keyword(s):  
Parameter Identification ◽  
Large Scale ◽  
Initial Conditions ◽  
Lithium Ion ◽  
Optimization Methods ◽  
Particle Model ◽  
Aerospace Applications ◽  
Novel Approach ◽  
Consistent Solution ◽  
The Common

Abstract Predicting the chemical and physical processes occurring in Lithium-ion cells with high-fidelity electrochemical models is today a critical requirement to accelerate the design and optimization of battery packs for automotive and aerospace applications. One of the common issues associated with electrochemical models is the complexity of parameter identification, particularly when relying only on experimental data obtained via non-invasive techniques. This paper presents a novel approach to improve the common methods of parameter calibration that consists of matching the predicted terminal voltage to test data via optimization methods. The study is conducted for an NMC-graphite cell, modeled using a reduced order Extended Single Particle Model (ESPM). The proposed approach relies on using a large-scale Particle Swarm Optimization (PSO), modified by including a term that accounts for the parameter sensitivity information, such that the rate of convergence and robustness of the algorithm to obtain a consistent solution in the presence of uncertainties in the initial conditions are significantly improved.

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